Cyclic peptide surface feature mimics of endothelin

Abstract

Cyclic peptides and pharmaceutically acceptable salts and esters thereof are provided. The cyclic peptides and pharmaceutically acceptable salts and esters thereof mimic surface features of the C-terminus of endothelin and thereby can be used modulate or alter the activity of the endothelin family of peptides. More particularly, cyclic pentapeptides, cyclic hexapeptides, cyclic heptapeptides and pharmaceutically acceptable derivatives of the peptides that specifically inhibit the activity of endothelin are provided. Among the cyclic peptides are those that have the formula: cyclo(X 1 -X 2 -X 3 -X 4 -D-Trp): X 1 is D-Tyr or D-Asp; X 2 is Phe, Ala, Ac 3 c or Pro; X 3 is D-His, D-Ala, D-Val, Gly or β-Ala; and X 4 is His, Ala, β-Ala, Aib, Gly, D-His-gly or Leu; cyclo(X 1 -L-Phe-X 3 -X 4 -X 5 ) in which X 1 is D-Tyr, D-Asp or D-Glu, X 3 is selected from among D-His, β-Ala-D-His or gly-D-His; X 4 is Ser, Gly or β-Ala, and X 5 is D-Trp or N-Me-D-Trp; cyclo(X 1 -X 2 -X 3 -X 4 -L-Trp) in which X 1 is D-Ala, Aib, Gly, D-Val, D-Leu, D-lle, D-Nva, D-Nle, or D-Alle; X 2 is D-Val, D-Leu, D-lle, D-Ala, D-Gln, Gly, Aib, D-Nva, D-Nle, or D-Alle; X 3 is Pro, Gly, Aib, Val, Leu, L-Nva, L-Nle, L-Alle or L-Hyp and X 4 is D-Asp, D-Glu, D-Ser, D-Thr, D-Tyr, D-Cys(O 3 H) or D-Pen(O 3 H); and cyclo(X 1 -X 2 -X 3 -X 4 -L-Trp) in which X 1 is D-Leu, D-Val, D-lle, D-Ala, Gly, Aib, D-Nva, D-Nle or D-Alle; X 2 is Val, lle, Leu, Ala, Gln, Gly, Aib, L-Nva, L-Nle or L-Alle; X 3 is D-Pro, D-Hyp, D-Ala, D-Val, D-lle, Gly, Aib, D-Nva, D-Nle or D-Alle; and X 4 is Asp, Glu, Tyr, Ser, Thr, L-Cys(O 3 H) or L-Pen(O 3 H). Pharmaceutical compositions containing the peptides and methods of modulating the activity of endothelin peptides are also provided.

We claim: 
     
       1. A substantially pure peptide of formula (III):   cyclo(X.sup.1 -X.sup.2 -X.sup.3 -X.sup.4 -L-Trp)           (III)     or a pharmaceutically acceptable salt thereof, wherein:   X 1  is D-Leu, D-Val, D-lle, D-Ala, Gly, Aib, D-Nva, D-Nle or D-Alle; X 2  is L-Val, L-lle, L-Leu, L-Ala, L-Gln, L-Gly, Aib, L-Nva, L-Nlle or L-Alle; X 3  is D-Pro, D-Hyp, D-Ala, D-Val, D-lle, Gly, Aib, D-Nva, D-Nle or D-Alle; and X 4  is L-Asp, L-Glu, L-Tyr, L-Ser, L-Thr, L-Cys(O 3   H ) or L-Pen(O 3  H).   
     
     
       2. A peptide of claim 1, wherein X 1  is D-Leu, D-Val, D-lle or D-Ala;   X 2  is L-Val, L-lle, L-Leu or L-Ala;   X 3  is D-Pro, D-Ala, D-Val or D-lle; and   X 4  is L-Asp, L-Glu, L-Tyr or L-Ser.   
     
     
       3. The peptides of claim 2, wherein: X  1  is D-Leu;   X  2  is L-Val, L-lle, L-Leu or L-Ala;   X  3  is D-Pro, D-Ala, D-Val or D-lle; and   X  4  is L-Asp, L-Glu, L-Tyr or L-Ser.   
     
     
       4. The peptides of claim 3, wherein: X 1  is D-Leu;   X 2  is L-Val;   X 3  is D-Pro, D-Ala, D-Val or D-lle; and   X 4  is L-Asp, L-Glu, L-Tyr or L-Ser.   
     
     
       5. A peptide of claim 4 selected from the group consisting of cyclo(D-Leu-L-Val-D-Pro-L-Tyr-L-Trp), cyclo(D-Leu-L-Val-D-Pro-L-Ser-L-Trp), cyclo(D-Leu-L-Val-D-Pro-L-Asp-L-Trp), cyclo(D-Leu-L-Val-D-Pro-L-Asp-L-Trp), cyclo(D-Leu-L-Val-D-Pro-L-Glu-L-Trp), cyclo(D-Leu-L-Val-D-Ala-L-Asp-L-Trp) and cyclo(D-Leu-L-Val-Gly-L-Asp-L-Trp). 
     
     
       6. A peptide of claim 5 that is D-Leu-L-Val-D-Pro-L-Asp-L-Trp or D-Leu-L-Val-D-Pro-L-Ser-L-Trp. 
     
     
       7. A pharmaceutical composition, comprising a peptide of claim 1, in a pharmaceutically acceptable vehicle. 
     
     
       8. The composition of claim 7, that is formulated for single dosage administration and that contains an amount of the peptide that is effective for ameliorating the symptoms of hypertension, cardiovascular disease, asthma, ophthalmologic disease, gastroenteric disease, renal failure, menstrual disorders, obstetric conditions, wounds, endotoxin shock, anaphylactic shock, or hemorrhagic shock. 
     
     
       9. A method for the treatment of endothelin-mediated diseases, comprising administering the composition of claim 8 to an individual wherein the effective amount is sufficient to ameliorate one or more symptoms of the endothelin-mediated disease. 
     
     
       10. An article of manufacture, comprising packaging material and a peptide of claim 1, contained within the packaging material, wherein the peptide is effective for antagonizing the effects of endothelin, ameliorating the symptoms of an endothelin-mediated disorder, or inhibiting the binding of an endothelin peptide to an ET receptor; and the packaging material includes a label that indicates that the peptide is used for antagonizing the effects of endothelin, inhibiting the binding of endothelin to an endothelin receptor or treating an endothelin-mediated disorder. 
     
     
       11. A method for inhibiting the binding of an endothelin peptide to endothelin A  (ET A ) or endothelin B  (ET B ) receptors, comprising contacting the receptors with an endothelin peptide and with one or more peptides of claim 1, wherein: the contacting with the one or more peptides is effected prior to, simultaneously with or subsequent to contacting the receptors with the endothelin peptide.   
     
     
       12. A method for altering endothelin receptor-mediated activity, comprising contacting endothelin receptors with one or more peptides of claim 1. 
     
     
       13. A pharmaceutical composition, comprising a peptide of claim 2 in a pharmaceutically acceptable vehicle. 
     
     
       14. The composition of claim 13, that is formulated for single dosage administration and that contains an amount of the peptide that is effective for ameliorating the symptoms of hypertension, cardiovascular disease, asthma, ophthalmologic disease, gastroenteric disease, renal failure, menstrual disorders, obstetric conditions, wounds, endotoxin shock, anaphylactic shock, or hemorrhagic shock. 
     
     
       15. A method for the treatment of endothelin-mediated diseases, comprising administering the composition of claim 14 to an individual wherein the effective amount is sufficient to ameliorate one or more symptoms of the endothelin-mediated disease. 
     
     
       16. An article of manufacture, comprising packaging material and a peptide of claim 2 contained within the packaging material, wherein the peptide is effective for antagonizing the effects of endothelin, ameliorating the symptoms of an endothelin-mediated disorder, or inhibiting the binding of an endothelin peptide to an ET receptor; and the packaging material includes a label that indicates that the peptide is used for antagonizing the effects of endothelin, inhibiting the binding of endothelin to an endothelin receptor or treating an endothelin-mediated disorder. 
     
     
       17. A method for inhibiting the binding of an endothelin peptide to endothelin A  (ET A ) or endothelin B  (ET B ) receptors, comprising contacting the receptors with an endothelin peptide and with one or more peptides of claim 2, wherein: the contacting with the one or more peptides is effected prior to, simultaneously with or subsequent to contacting the receptors with the endothelin peptide.   
     
     
       18. A method for altering endothelin receptor-mediated activity, comprising contacting endothelin receptors with one or more peptides of claim 2. 
     
     
       19. A pharmaceutical composition, comprising a peptide of claim 3 in a pharmaceutically acceptable vehicle. 
     
     
       20. The composition of claim 18, that is formulated for single dosage administration and that contains an amount of the peptide that is effective for ameliorating the symptoms of hypertension, cardiovascular disease, asthma, ophthalmologic disease, gastroenteric disease, renal failure, menstrual disorders, obstetric conditions, wounds, endotoxin shock, anaphylactic shock, or hemorrhagic shock. 
     
     
       21. A method for the treatment of endothelin-mediated diseases, comprising administering the composition of claim 20 to an individual wherein the effective amount is sufficient to ameliorate one or more symptoms of the endothelin-mediated disease. 
     
     
       22. An article of manufacture, comprising packaging material and a peptide of claim 3 contained within the packaging material, wherein the peptide is effective for antagonizing the effects of endothelin, ameliorating the symptoms of an endothelin-mediated disorder, or inhibiting the binding of an endothelin peptide to an ET receptor; and the packaging material includes a label that indicates that the peptide is used for antagonizing the effects of endothelin, inhibiting the binding of endothelin to an endothelin receptor or treating an endothelin-mediated disorder. 
     
     
       23. A method for inhibiting the binding of an endothelin peptide to endothelin A  (ET A ) or endothelin B  (ET B ) receptors, comprising contacting the receptors with an endothelin peptide and with one or more peptides of claim 3, wherein: the contacting with one or more peptides is effected prior to, simultaneously with or subsequent to contacting the receptors with the endothelin peptide.   
     
     
       24. A method for altering endothelin receptor-mediated activity, comprising contacting endothelin receptors with one or more peptides of claim 3. 
     
     
       25. A pharmaceutical composition, comprising a peptide of claim 4 in a pharmaceutically acceptable vehicle. 
     
     
       26. The composition of claim 25, that is formulated for single dosage administration and that contains an amount of the peptide that is effective for ameliorating the symptoms of hypertension, cardiovascular disease, asthma, ophthalmologic disease, gastroenteric disease, renal failure, menstrual disorders, obstetric conditions, wounds, endotoxin shock, anaphylactic shock, or hemorrhagic shock. 
     
     
       27. A method for the treatment of endothelin-mediated diseases, comprising administering the composition of claim 26 to an individual wherein the effective amount is sufficient to ameliorate one or more symptoms of the endothelin-mediated disease. 
     
     
       28. An article of manufacture, comprising packaging material and a peptide of claim 4 contained within the packaging material, wherein the peptide is effective for antagonizing the effects of endothelin, ameliorating the symptoms of an endothelin-mediated disorder, or inhibiting the binding of an endothelin peptide to an ET receptor; and the packaging material includes a label that indicates that the peptide is used for antagonizing the effects of endothelin, inhibiting the binding of endothelin to an endothelin receptor or treating an endothelin-mediated disorder. 
     
     
       29. A method for inhibiting the binding of an endothelin peptide to endothelin A  (ET A ) or endothelin B  (ET B ) receptors, comprising contacting the receptors with an endothelin peptide and with one or more peptides of claim 4, wherein: the contacting with the one or more peptides is effected prior to, simultaneously with or subsequent to contacting the receptors with the endothelin peptide.   
     
     
       30. A method for altering endothelin receptor-mediated activity, comprising contacting endothelin receptors with one or more peptides of claim 4. 
     
     
       31. A pharmaceutical composition, comprising a peptide of claim 5 in a pharmaceutically acceptable vehicle. 
     
     
       32. The composition of claim 31, that is formulated for single dosage administration and that contains an amount of the peptide that is effective for ameliorating the symptoms of hypertension, cardiovascular disease, asthma, ophthalmologic disease, gastroenteric disease, renal failure, menstrual disorders, obstetric conditions, wounds, endotoxin shock, anaphylactic shock, or hemorrhagic shock. 
     
     
       33. A method for the treatment of endothelin-mediated diseases, comprising administering the composition of claim 32 to an individual wherein the effective amount is sufficient to ameliorate one or more symptoms of the endothelin-mediated disease. 
     
     
       34. An article of manufacture, comprising packaging material and a peptide of claim 5 contained within the packaging material, wherein the peptide is effective for antagonizing the effects of endothelin, ameliorating the symptoms of an endothelin-mediated disorder, or inhibiting the binding of an endothelin peptide to an ET receptor; and the packaging material includes a label that indicates that the peptide is used for antagonizing the effects of endothelin, inhibiting the binding of endothelin to an endothelin receptor or treating an endothelin-mediated disorder. 
     
     
       35. A method for inhibiting the binding of an endothelin peptide to endothelin A  (ET A ) or endothelin B  (ET B ) receptors, comprising contacting the receptors with an endothelin peptide and with one or more peptides of claim 5, wherein: the contacting with the one or more peptides is effected prior to, simultaneously with or subsequent to contacting the receptors with the endothelin peptide.   
     
     
       36. A method for altering endothelin receptor-mediated activity, comprising contacting endothelin receptors with one or more peptides of claim 5. 
     
     
       37. A pharmaceutical composition, comprising a peptide of claim 6 in a pharmaceutically acceptable vehicle. 
     
     
       38. The composition of claim 37, that is formulated for single dosage administration and that contains an amount of the peptide that is effective for ameliorating the symptoms of hypertension, cardiovascular disease, asthma, ophthalmologic disease, gastroenteric disease, renal failure, menstrual disorders, obstetric conditions, wounds, endotoxin shock, anaphylactic shock, or hemorrhagic shock. 
     
     
       39. A method for the treatment of endothelin-mediated diseases, comprising administering the composition of claim 37 to an individual wherein the effective amount is sufficient to ameliorate one or more symptoms of the endothelin-mediated disease. 
     
     
       40. An article of manufacture, comprising packaging material and a peptide of claim 6 contained within the packaging material, wherein the peptide is effective for antagonizing the effects of endothelin, ameliorating the symptoms of an endothelin-mediated disorder, or inhibiting the binding of an endothelin peptide to an ET receptor; and the packaging material includes a label that indicates that the peptide is used for antagonizing the effects of endothelin, inhibiting the binding of endothelin to an endothelin receptor or treating an endothelin-mediated disorder. 
     
     
       41. A method for inhibiting the binding of an endothelin peptide to endothelin A  (ET A ) or endothelin B  (ET B ) receptors, comprising contacting the receptors with an endothelin peptide and with one or more peptides of claim 6, wherein: the contacting with the one or more peptides is effected prior to, simultaneously with or subsequent to contacting the receptors with the endothelin peptide.